Authors:Karit Reinson; Kadi Künnapas; Annika Kriisa; Mari-Anne Vals; Kai Muru; Katrin ÕunapPages: 1 - 5Abstract: Publication date: June 2018 Source:Molecular Genetics and Metabolism Reports, Volume 15 Author(s): Karit Reinson, Kadi Künnapas, Annika Kriisa, Mari-Anne Vals, Kai Muru, Katrin Õunap Vitamin B12 deficiency seems to be more common worldwide than previously thought. However, only a few reports based on data from newborn screening (NBS) programs have drawn attention to that subject. In Estonia, over the past three years, we have diagnosed 14 newborns with congenital acquired vitamin B12 deficiency. Therefore, the incidence of that condition is 33.8/100,000 live births, which is considerably more than previously believed. None of the newborns had any clinical symptoms associated with vitamin B12 deficiency before the treatment, and all biochemical markers normalized after treatment, which strongly supports the presence of treatable congenital deficiency of vitamin B12. During the screening period, we began using actively ratios of some metabolites like propionylcarnitine (C3) to acetylcarnitine (C2) and C3 to palmitoylcarnitine (C16) to improve the identification of newborns with acquired vitamin B12 deficiency. In the light of the results obtained, we will continue to screen the congenital acquired vitamin B12 deficiency among our NBS program. Every child with aberrant C3, C3/C2 and C3/C16 will be thoroughly examined to exclude acquired vitamin B12 deficiency, which can easily be corrected in most cases.

Authors:Raja Majid Afzal; Allan Meldgaard Lund; Flemming SkovbyPages: 6 - 10Abstract: Publication date: June 2018 Source:Molecular Genetics and Metabolism Reports, Volume 15 Author(s): Raja Majid Afzal, Allan Meldgaard Lund, Flemming Skovby Inborn errors of metabolism (IEM) are a heterogeneous group of genetic disorders present in all ethnic groups. We investigated the frequency of consanguinity among parents of newborns with IEM diagnosed by neonatal screening. Data were obtained from 15years of expanded newborn screening for selected IEM with autosomal recessive mode of inheritance, a national screening program of newborns covering the period from 2002 until April 2017. Among the 838,675 newborns from Denmark, the Faroe Islands and Greenland, a total of 196 newborns had an IEM of whom 155 from Denmark were included in this study. These results were crosschecked against medical records. Information on consanguinity was extracted from medical records and telephone contact with the families. Among ethnic Danes, two cases of consanguinity were identified in 93 families (2.15%). Among ethnic minorities there were 20 cases of consanguinity among 33 families (60.6%). Consequently, consanguinity was 28.2 times more frequent among descendants of other geographic place of origin than Denmark. The frequency of consanguinity was conspicuously high among children of Pakistani, Afghan, Turkish and Arab origin (71.4%). The overall frequency of IEM was 25.5 times higher among children of Pakistani, Turkish, Afghan and Arab origin compared to ethnic Danish children (5.35:10,000 v 0.21:10,000). The frequency of IEM was 30-fold and 50-fold higher among Pakistanis (6.5:10,000) and Afghans (10.6:10,000), respectively, compared to ethnic Danish children. The data indicate a strong association between consanguinity and IEM. These figures could be useful to health professionals providing antenatal, pediatric, and clinical genetic services.

Authors:Hyung-Ok Lee; Liqun Wang; Yin-Ming Kuo; Andrew J. Andrews; Sapna Gupta; Warren D. KrugerPages: 15 - 21Abstract: Publication date: June 2018 Source:Molecular Genetics and Metabolism Reports, Volume 15 Author(s): Hyung-Ok Lee, Liqun Wang, Yin-Ming Kuo, Andrew J. Andrews, Sapna Gupta, Warren D. Kruger Elevated plasma total homocysteine (tHcy) is associated with a number of human diseases including coronary artery disease, stroke, osteoporosis and dementia. It is highly correlated with intracellular S-adenosylhomocysteine (SAH). Since SAH is a strong inhibitor of methyl-transfer reactions involving the methyl-donor S-adenosylmethionine (SAM), elevation in SAH could be an explanation for the wide association of tHcy and human disease. Here, we have created a transgenic mouse (Tg-hAHCY) that expresses human S-adenosylhomocysteine hydrolase (AHCY) from a zinc-inducible promoter in the liver and kidney. Protein analysis shows that human AHCY is expressed well in both liver and kidney, but elevated AHCY enzyme activity (131% increase) is only detected in the kidney due to the high levels of endogenous mouse AHCY expression in liver. Tg-hAHCY mice were crossed with mice lacking cystathionine β-synthase activity (Tg-I278T Cbs −/− ) to explore the effect to AHCY overexpression in the context of elevated serum tHcy and elevated tissue SAM and SAH. Overexpression of AHCY had no significant effect on the phenotypes of Tg-I278T Cbs −/− mice or any effect on the steady state concentrations of methionine, total homocysteine, SAM, SAH, and SAM/SAH ratio in the liver and kidney. Furthermore, enhanced AHCY activity did not lower serum and tissue tHcy or methionine levels. Our data suggests that enhancing AHCY activity does not alter the distribution of methionine recycling metabolites, even when they are greatly elevated by Cbs mutations.

Authors:Yuka Hiroshima; Takenori Yamamoto; Masahiro Watanabe; Yoshinobu Baba; Yasuo ShinoharaPages: 36 - 42Abstract: Publication date: June 2018 Source:Molecular Genetics and Metabolism Reports, Volume 15 Author(s): Yuka Hiroshima, Takenori Yamamoto, Masahiro Watanabe, Yoshinobu Baba, Yasuo Shinohara Brown adipose tissue (BAT) plays an important role in regulation of energy expenditure while adapting to a cold environment. BAT thermogenesis depends on uncoupling protein 1 (UCP1), which is expressed in the inner mitochondrial membranes of BAT. Gene expression profiles induced by cold exposure in BAT have been studied, but the metabolomic biological pathway that contributes to the activation of thermogenesis in BAT remains unclear. In this study, we comprehensively compared the relative levels of metabolites between the BAT of rats kept at room temperature (22 °C) and of those exposed to a cold temperature (4 °C) for 48 h using capillary electrophoresis (CE) time-of-flight mass spectrometry (TOFMS) and liquid chromatography (LC)-TOFMS. We identified 218 metabolites (137 cations and 81 anions) by CE-TOFMS and detected 81 metabolites (47 positive and 34 negative) by LC-TOFMS in BAT. We found that cold exposure highly influenced the BAT metabolome. We showed that the cold environment lead to lower levels of glycolysis and gluconeogenesis intermediates and higher levels of the tricarboxylic acid (TCA) cycle metabolites, fatty acids, and acyl-carnitine metabolites than control conditions in the BAT of rats. These results indicate that glycolysis and β-oxidation of fatty acids in BAT are positive biological pathways that contribute to the activation of thermogenesis by cold exposure, thereby facilitating the generation of heat by UCP1. These data provide useful information for understanding the basal metabolic functions of BAT thermogenesis in rats in response to cold exposure.

Authors:Max Sugarman; Jamil Choudhury; Ana JovanovicPages: 43 - 45Abstract: Publication date: June 2018 Source:Molecular Genetics and Metabolism Reports, Volume 15 Author(s): Max Sugarman, Jamil Choudhury, Ana Jovanovic Fabry disease is an X-linked metabolic disorder resulting in widespread deposition of Globotriaosylceramide within a variety of human tissues. The classical Fabry phenotype is one of early onset disease, with extensive tissue involvement resulting in acroparaesthesia, gastrointestinal disturbances, angiokeratoma, cornea verticillata renal failure, and cardiovascular disease. We describe two brothers exhibiting the GLA p.N215S mutation, a variant most often conferring a late-onset disease confined to the myocardium. The proband was diagnosed aged 34, following investigation into proteinuria. Despite Enzyme Replacement Therapy, he progressed to end-stage renal failure, and subsequently received a renal transplant. He also developed hypertrophic cardiomyopathy. His sibling however, whose disease was detected aged 32 following screening, exhibits mild left ventricular hypertrophy, and no evidence of renal disease. He remains clinically asymptomatic. This case report details a discordant phenotype in brothers with Fabry disease and p.N215S mutation. Despite the fact that in the majority of patients this mutation is associated with a late onset presentation with hypertrophic cardiomyopathy, we have clearly demonstrated that patients with GLA p.N215S mutation can present with the classical phenotype. Further studies are required to elucidate the underlying modifying factors that influence clinical presentation with a more severe phenotype.

Authors:Zuhair N. Al-Hassnan; Ola A. Khalifa; Dalal K. Bubshait; Sahar Tulbah; Maarab Alkorashy; Hamad Alzaidan; Mohammed Alowain; Zuhair Rahbeeni; Moeen Al-SayedPages: 50 - 54Abstract: Publication date: June 2018 Source:Molecular Genetics and Metabolism Reports, Volume 15 Author(s): Zuhair N. Al-Hassnan, Ola A. Khalifa, Dalal K. Bubshait, Sahar Tulbah, Maarab Alkorashy, Hamad Alzaidan, Mohammed Alowain, Zuhair Rahbeeni, Moeen Al-Sayed Infantile-Onset Pompe Disease (IOPD) is an autosomal recessive disorder of glycogen metabolism resulting from deficiency of the lysosomal hydrolase acid α-glucosidase encoded by GAA gene. Affected infants present before the age of 12 months with hypotonia, muscle weakness, and hypertrophic cardiomyopathy. Enzyme replacement therapy (ERT) has been shown to improve survival, cardiac mass, and motor skills. In this work, we aim to illustrate the genotypes of IOPD and the outcome of ERT in our population. The medical records of infants with confirmed diagnosis of IOPD who received ERT were reviewed. Eighteen infants (7 males, 11 females) were included in the study. The median age at presentation was 2 months and the median age at the start of ERT was 4.5 months. Fifteen (83.3%) infants died with a median age at death of 12 months. The 3 alive infants (whose current ages are 6½ years, 6 years, and 10 years), who were initiated on ERT at the age of 3 weeks, 5 months, and 8 months respectively, has had variable response with requirement of assisted ventilation in one child and tracheostomy in another child. All infants were homozygous for GAA mutations except one infant who was compound heterozygous. All infants (n = 8) with truncating mutations died. Our work provides insight into the correlation of genotypes and outcome of ERT in IOPD in Saudi Arabia. Our data suggest that early detection of cases, through newborn screening, and immunomodulation before the initiation of ERT may improve the outcome of ERT in Saudi infants with IOPD.

Authors:Yasuyuki Fukuhara; Naoko Fuji; Narutoshi Yamazaki; Asami Hirakiyama; Tetsuharu Kamioka; Joo-Hyun Seo; Ryuichi Mashima; Motomichi Kosuga; Torayuki OkuyamaPages: 3 - 9Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Yasuyuki Fukuhara, Naoko Fuji, Narutoshi Yamazaki, Asami Hirakiyama, Tetsuharu Kamioka, Joo-Hyun Seo, Ryuichi Mashima, Motomichi Kosuga, Torayuki Okuyama Pompe disease is an autosomal recessive disorder caused by acid α-glucosidase (GAA) deficiency, which results in the accumulation of glycogen in lysosomes in multiple tissues, including cardiac, skeletal, and smooth muscle cells. Thus far, 558 sequence variants of the GAA gene have been published in the Pompe Disease Mutation Database, and some mutations appear with considerable frequency in particular ethnic groups, such as Caucasians, Taiwanese, Chinese, and Koreans. However, the GAA mutation pattern in Japanese patients remains poorly understood. We analyzed the relationship between the genetic and clinical features of 38 mostly Japanese patients with Pompe disease from 35 unrelated families. We identified 28 different GAA gene mutations, including 7 novel mutations, by a GAA gene analysis. c.546G>T (22.9%) and c.1857C>G (14.3%) were the most common mutations and accounted for 37.1% of the total mutant alleles. In the six patients with infantile-onset Pompe disease (IOPD), c.1857C>G was also the most common mutation. In addition, there were 13 homozygotes (5 with the c.546G>T) among the 35 families, which is the highest frequency reported thus far. Regarding the initial symptoms, cardiomegaly was the most common (3/6=50%) in IOPD patients, while muscle weakness was observed the most frequently in patients with late-onset Pompe disease (LOPD) (15/30=50%). Notably, all IOPD patients who showed respiratory distress at the time of onset require respiratory assistance at present (4/4=100%). Regarding the presenting symptoms, cardiomegaly (6/6=100%) and hepatomegaly (4/6=66.7%) were more commonly seen in IOPD, and muscle weakness (24/29=82.7%) was observed more frequently in LOPD. Respiratory assistance is required at present in 33.3% of IOPD patients and 50% of LOPD patients, and 20% of IOPD patients and 29.6% of LOPD patients are wheelchair users. These individual clinical courses may be influenced by the timing of the diagnosis and treatment; for example, in 2007, an ERT orphan drug for treatment of Pompe disease, Alglucosidase alfa, was made available in Japan, and there were 5 (5/6=83.3%) wheelchair users diagnosed from 2008 to 2009 (cases 32–38) and 4 (4/27=14.8%) from 2010 to 2015 (cases 1–31). These findings underscore the importance of the early diagnosis and treatment.

Authors:Ryuichi Mashima; Mari Ohira; Torayuki Okuyama; Akiya TatsumiPages: 36 - 40Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Ryuichi Mashima, Mari Ohira, Torayuki Okuyama, Akiya Tatsumi Mucopolysaccharidosis (MPS) is a genetic disorder characterized by the accumulation of glycosaminoglycans in the body. Of the multiple MPS disease subtypes, several are caused by defects in sulfatases. Specifically, a defect in iduronate-2-sulfatase (ID2S) leads to MPS II, whereas N-acetylgalactosamine-6-sulfatase (GALN) and N-acetylgalactosamine-4-sulfatase (ARSB) defects relate to MPS IVA and MPS VI, respectively. A previous study reported a combined assay for these three disorders in a 96-well plate using a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based technique (Kumar et al., Clin Chem 2015 61(11):1363-1371). In our study, we applied this methodology to a Japanese population to examine the assay precision and the separation of populations between disease-affected individuals and controls for these three disorders. Within our assay conditions, the coefficient of variation (CV, %) values for an interday assay of ID2S, GALN, and ARSB were 9%, 18%, and 9%, respectively (n =7). The average enzyme activities of ID2S, GALN, and ARSB in random neonates were 19.6±5.8, 1.7±0.7, and 13.4±5.2μmol/h/L (mean±SD, n =240), respectively. In contrast, the average enzyme activities of ID2S, GALN, and ARSB in disease-affected individuals were 0.5±0.2 (n =6), 0.3±0.1 (n =3), and 0.3 (n =1) μmol/h/L, respectively. The representative analytical range values corresponding to ID2S, GALN, and ARSB were 39, 17, and 168, respectively. These results raise the possibility that the population of disease-affected individuals could be separated from that of healthy individuals using the LC-MS/MS-based technique.

Authors:Elena Voskoboeva; Alla Semyachkina; Maria Yablonskaya; Ekaterina NikolaevaPages: 47 - 54Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Elena Voskoboeva, Alla Semyachkina, Maria Yablonskaya, Ekaterina Nikolaeva We present the results of the 45-year clinical observation of 27 Russian homocystinuria patients. We made a mutation analysis of the CBS gene for thirteen patients from eleven unrelated genealogies. All patients except for the two were compound heterozygotes for the mutations detected. The most frequent mutation in the cohort investigated was splice mutation IVS11-2a->c. We detected one new nonsense mutation, one new missense-mutation and three novel small deletions. We also report the clinical case of the B6-responsive patient genotyped as Ile278Thr/Cys109Arg.

Authors:Ida Vanessa D. Schwartz; Özlem Göker-Alpan; Priya S. Kishnani; Ari Zimran; Lydie Renault; Zoya Panahloo; Patrick DeeganPages: 73 - 79Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Ida Vanessa D. Schwartz, Özlem Göker-Alpan, Priya S. Kishnani, Ari Zimran, Lydie Renault, Zoya Panahloo, Patrick Deegan The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. Historically, there has been a limited understanding of type 3 GD (GD3) and its natural history in patients irrespective of their treatment status. Here, we describe the disease characteristics of patients with GD3 enrolled in GOS. As of October 2015, 1002 patients had been enrolled, 26 of whom were reported as GD3. The majority of patients with GD3 were from the US (13; 50.0%), seven (26.9%) were from the UK, three (11.5%) from Israel, and three (11.5%) from Brazil. No patients were of Ashkenazi Jewish origin. Median age of symptom onset was 1.4 (interquartile range: 0.5–2.0) years. The most common GBA1 mutation genotype was L444P/L444P, occurring in 16 (69.6%) of 23 patients who had genotyping information available. Nine patients reported a family history of GD (any type). Of 21 patients with treatment status information, 20 (95.2%) had received GD-specific treatment at any time, primarily imiglucerase (14 patients) and/or velaglucerase alfa (13 patients). Hemoglobin concentrations and platelet counts at GOS entry were within normal ranges for most patients, and there were no reports of severe hepatomegaly or of splenomegaly in non-splenectomized patients, most likely indicative of the effects of treatment received prior to GOS entry. This analysis provides information on the characteristics of patients with GD3 that could be used as the baseline for longitudinal follow-up of these patients.

Authors:Sharon Evans; Anne Daly; Satnam Chahal; Catherine Ashmore; John MacDonald; Anita MacDonaldPages: 10 - 14Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Sharon Evans, Anne Daly, Satnam Chahal, Catherine Ashmore, John MacDonald, Anita MacDonald Background In a previous case-control study, we demonstrated that children with PKU and non-PKU controls preferred sweet foods. Additionally, children with PKU exhibited food neophobia, with no preference for bitter tasting foods associated with the taste of phenylalanine (Phe)-free L-amino acid supplements. Objective In an observational extension study, we evaluated the influence of parental food choice and neophobia on their children's taste preferences and food neophobia. Methods Male and female parents/caregivers of 35 children with PKU and 35 control parents, completed a neophobia and food frequency questionnaire for comparison using the same questionnaires that they completed for their children. Results Both groups of children (PKU and non PKU control) were rated as more food neophobic and exhibited more neophobic behaviour than parents, although children with PKU more so than non-PKU controls (PKU food neophobia p<0.0001vs control 0.001; PKU general neophobia p=0.003 vs control p=0.04). Both groups of children ate significantly more sweets, sweetened drinks and potato fries than their parents but differences were greater for children with PKU who also consumed more high carbohydrate (low protein) staple foods such as bread and pasta, and more sweet snacks such as biscuits than their parents. Non-PKU control children's food choices were closer to their parent's choices. Conclusions In PKU, parental food choices and their food neophobia have limited influence on their children's eating habits. Food neophobia in children with PKU may be associated with fear of eating unfamiliar foods potentially containing a source of protein or aspartame. Their preference for sweet foods may be influenced by limited food choices and habitual consumption of artificially sweetened L-amino acid supplements.

Authors:Niamh Finnigan; Jane Roberts; Jean Mercer; Simon A. JonesPages: 15 - 18Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Niamh Finnigan, Jane Roberts, Jean Mercer, Simon A. Jones Enzyme replacement therapy is the only available treatment for Mucopolysaccharidosis type IVA (MPS IVA, Morquio syndrome). The treatment is lengthy and invasive involving weekly intravenous infusions of 4–5h. This can cause significant disruption to normal family life so the provision of a safe and effective homecare service is essential. In order to deliver a safe service, robust standards must be in place; this includes appropriately trained members of homecare staff, detailed management for infusion related reactions (IRR) and appropriate venous access. In this report we demonstrate the criteria required to ensure a successful home treatment programme and describe our experience thus far.

Authors:Josef Finsterer; Claudia StöllbergerPages: 19 - 21Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Josef Finsterer, Claudia Stöllberger Objectives According to recent publications, some patients with spinal and bulbar muscular atrophy (BSMA) develop cardiac disease, manifesting as ST-segment abnormalities, Brugada-syndrome, dilative cardiomyopathy, or sudden cardiac death. Here we present neurological and cardiac data of a BSMA patient who was followed up for 10y. Case report In a male patient aged 47y, BSMA was diagnosed at age 37y upon the typical clinical presentation (postural tremor since age 12y, dysarthria since age 15y, muscle cramps since age 29y, general myalgias since age 32y, general fasciculations since age 34y, myoclonic jerks, easy fatigability, dyspnea upon exercise since age 36y) and a CAG-repeat expansion of 47±1 repeats in the androgen-receptor gene detected at age 37y. During the next 10y he additionally developed mild but slowly progressive diffuse weakness on the upper limbs and mild proximal weakness on the lower limbs. Cardiologic exam, ECG, and echocardiography were normal at ages 37y, 41y, 44y, and 47y. Conclusions Cardiac involvement may only develop in some BSMA patients within 10y, whereas neurologic abnormalities slowly progress within 10y of observation. Cardiac disease may develop at a later stage with progression of age and disease.

Authors:Josef Finsterer; Claudia StöllbergerPages: 19 - 21Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Josef Finsterer, Claudia Stöllberger Objectives According to recent publications, some patients with spinal and bulbar muscular atrophy (BSMA) develop cardiac disease, manifesting as ST-segment abnormalities, Brugada-syndrome, dilative cardiomyopathy, or sudden cardiac death. Here we present neurological and cardiac data of a BSMA patient who was followed up for 10y. Case report In a male patient aged 47y, BSMA was diagnosed at age 37y upon the typical clinical presentation (postural tremor since age 12y, dysarthria since age 15y, muscle cramps since age 29y, general myalgias since age 32y, general fasciculations since age 34y, myoclonic jerks, easy fatigability, dyspnea upon exercise since age 36y) and a CAG-repeat expansion of 47±1 repeats in the androgen-receptor gene detected at age 37y. During the next 10y he additionally developed mild but slowly progressive diffuse weakness on the upper limbs and mild proximal weakness on the lower limbs. Cardiologic exam, ECG, and echocardiography were normal at ages 37y, 41y, 44y, and 47y. Conclusions Cardiac involvement may only develop in some BSMA patients within 10y, whereas neurologic abnormalities slowly progress within 10y of observation. Cardiac disease may develop at a later stage with progression of age and disease.

Authors:Gregory Costain; Aideen M. Moore; Lauren Munroe; Alison Williams; Randi Zlotnik Shaul; Cheryl Rockman-Greenberg; Martin Offringa; Peter KannuPages: 22 - 26Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Gregory Costain, Aideen M. Moore, Lauren Munroe, Alison Williams, Randi Zlotnik Shaul, Cheryl Rockman-Greenberg, Martin Offringa, Peter Kannu Enzyme replacement therapy (ERT) is a newly approved disease-modifying treatment for hypophosphatasia (HPP), a rare metabolic bone disorder. With an orphan drug and ultra-rare disease, sharing information about responders and non-responders is particularly important, as any one centre's familiarity with its use will be limited. Nearly all published data in infants and very young children with life-threatening HPP are from three small clinical trials that have reported generally positive outcomes. We describe in detail a patient with perinatal HPP for whom treatment with ERT was not successful. Lessons learned from this case can inform clinical decision-making and provide topics for the research agenda. We also discuss practical and ethical challenges related to treatment of an ultra-rare disease with an expensive new medication in a publicly funded healthcare system.

Authors:Adina H. Wise; Amy Yang; Hetanshi Naik; Chanan Stauffer; Natasha Zeid; Christopher Liong; Manisha Balwani; Robert J. Desnick; Roy N. AlcalayPages: 27 - 30Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Adina H. Wise, Amy Yang, Hetanshi Naik, Chanan Stauffer, Natasha Zeid, Christopher Liong, Manisha Balwani, Robert J. Desnick, Roy N. Alcalay Recent research has suggested a possible link between Parkinson's disease (PD) and Fabry disease. To test this relationship, we administered a self-report and family history questionnaire to determine the prevalence of PD in Fabry disease patients and family members with likely pathogenic alpha-galactosidase A (GLA) mutations. A total of 90 Fabry patients (77 from the online survey and 13 from the Icahn School of Medicine at Mount Sinai (ISMMS)) were included in the analysis. Two of the Fabry disease patients who completed the online survey were diagnosed with PD (2/90, 2.2%). Among probands older than 60, 8.3% (2/24) were diagnosed with PD. Using Kaplan Meier survival analysis, the age-specific risk of PD by age 70 was 11.1%. Family history was available on 72 Fabry families from the online study and 9 Fabry families from ISMMS. Among these 81 families, 6 (7.4%) had one first degree relative who fit the criteria for a conservative diagnosis of PD. The results of this study suggest that there may be an increased risk of developing PD in individuals with GLA mutations, but these findings should be interpreted with caution given the limitations of the study design.

Authors:Caitlin Doherty; Lauren W. Averill; Mary Theroux; William G. Mackenzie; Christian Pizarro; Robert W. Mason; Shunji TomatsuPages: 59 - 67Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Caitlin Doherty, Lauren W. Averill, Mary Theroux, William G. Mackenzie, Christian Pizarro, Robert W. Mason, Shunji Tomatsu Morquio A syndrome (mucopolysaccharidosis IVA, MPS IVA) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase, resulting in systemic accumulation of the partially degraded glycosaminoglycans (GAGs), keratan sulfate and chondroitin-6-sulfate. The accumulation of these GAGs leads to distinguishing features as skeletal dysplasia with disproportionate dwarfism, short neck, kyphoscoliosis, pectus carinatum, tracheal obstruction, coxa valga, genu valgum, and joint laxity. In the absence of autopsied cases and systemic analysis of multiple tissues, the pathological mechanism of the characteristic skeletal dysplasia associated with the disease largely remains a question. Here we report an autopsied case of a 23-year-old male with MPS IVA, who developed characteristic skeletal abnormalities by 4months of age and died of severe tracheal obstruction and hypoventilation originating from respiratory muscle weakness from neurological cord deficit due to cord myelopathy at the age of 23. We analyzed postmortem tissues pathohistologically, including the thyroid, lung, lung bronchus, trachea, heart, aorta, liver, spleen, kidney, testes, humerus, knee cartilage, and knee ligament. Examination of the tissues demonstrated systemic storage materials in multiple tissues, as well as severely ballooned and vacuolated chondrocytes in the trachea, humerus, knee cartilage, and lung bronchus. This autopsied case with MPS IVA addresses the importance of tracheal obstruction for morbidity and mortality of the disease, and the pathological findings contribute to a further understanding of the pathogenesis of MPS IVA and the development of novel therapies.

Authors:Jun Okada; Mohammad Arif Hossain; Chen Wu; Takashi Miyajima; Hiroko Yanagisawa; Keiko Akiyama; Yoshikatsu EtoPages: 68 - 72Abstract: Publication date: March 2018 Source:Molecular Genetics and Metabolism Reports, Volume 14 Author(s): Jun Okada, Mohammad Arif Hossain, Chen Wu, Takashi Miyajima, Hiroko Yanagisawa, Keiko Akiyama, Yoshikatsu Eto Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-gal A), leading to the progressive accumulation of glycosphingolipids. Classical hemizygous males usually present symptoms, including pain and paresthesia in the extremities, angiokeratoma, hypo- or anhidrosis, abdominal pain, cornea verticillata, early stroke, tinnitus, and/or hearing loss, during early childhood or adolescence. Moreover, proteinuria, renal impairment, and cardiac hypertrophy can appear with age. Enzyme replacement is the most common therapy for Fabry disease at present which has been approved in Japan since 2004. We report a case involving a 27-year-old male with extreme terminal pain, anhidrosis, abdominal pain, tinnitus, hearing impairment, cornea verticillata, and recurrent huge ulcers in the lower extremities. At the age of 16years, he was diagnosed with Fabry disease with a positive family history and very low α-gal A activity. He then received enzyme replacement therapy (ERT) with recombinant human agalsidase beta at 1mg/kg every 2weeks for 10years. Throughout the course of ERT, his leg ulcers recurred, and massive excretion of urinary globotriaosylceramide and plasma globotriaosylsphingosine was observed. Electron microscopy of the venous tissue in the regions of the ulcer showed massive typical zebra bodies in the vascular wall smooth muscle cells.

Authors:Karolina M. Stepien; Chris J. HendrikszPages: 3 - 6Abstract: Publication date: December 2017 Source:Molecular Genetics and Metabolism Reports, Volume 13 Author(s): Karolina M. Stepien, Chris J. Hendriksz Background Fabry disease, an X-linked genetic condition, results from alpha-galactosidase deficiency and increased accumulation of glycosphingolipids in cardiovascular tissues. Clinical manifestation includes vasculature associated complications. Hyperlipidaemia is one of the cardiovascular risk factors however it has never been well defined in Fabry disease. Enzyme Replacement Therapy (ERT) is available but its effect on serum cholesterol is unknown. The aim of this project was to assess the influence of long-term ERT on lipid profile in a large cohort of adult patients with Fabry disease. Methods This was a retrospective analysis of lipid profile results. Patients with Fabry disease were on ERT for 10years, were not treated with statins and had no severe renal impairment. All patients had lipid profile measured before ERT was commenced and 6, 12, 24, 36, 48, 60, 120months later. Statistical analysis included ANOVA, Student t-test and descriptive statistics. Results Among 72 patients, 40 were females (median age 45; range 29–75), 32 males (median age 46; range 20–69). There was no significant difference in total cholesterol or HDL-cholesterol measured at baseline before ERT was commenced and 6, 12, 24, 36, 48, 60 and 120months after ERT was commenced in 72 patients (ANOVA; P =0.673 and P =0.883, respectively). Female patients on ERT had higher mean HDL-cholesterol as compared to female patients with Fabry disease who were asymptomatic and not treated (P ≥0.05). Total cholesterol between treated and non-treated female patients was comparable. Female patients on ERT have higher total cholesterol and HDL-cholesterol when compared to lipid results in male patients on ERT. Total cholesterol/HDL-cholesterol ratio was low in female and male patients on ERT over 10years. Conclusion Adult patients with Fabry disease have remarkably elevated HDL-cholesterol and as a result, elevated total cholesterol. It is possible that elevated HDL-cholesterol has a cardioprotective effect in patients with this condition. Long term ERT does not have a significant impact on lipid profile in female and male population with Fabry disease.

Authors:Han-Hyuk Lim; Haiqing Yi; Takashi K. Kishimoto; Fengqin Gao; Baodong Sun; Priya S. KishnaniPages: 18 - 22Abstract: Publication date: December 2017 Source:Molecular Genetics and Metabolism Reports, Volume 13 Author(s): Han-Hyuk Lim, Haiqing Yi, Takashi K. Kishimoto, Fengqin Gao, Baodong Sun, Priya S. Kishnani A major obstacle to enzyme replacement therapy (ERT) with recombinant human acid-α-glucosidase (rhGAA) for Pompe disease is the development of high titers of anti-rhGAA antibodies in a subset of patients, which often leads to a loss of treatment efficacy. In an effort to induce sustained immune tolerance to rhGAA, we supplemented the rhGAA therapy with a weekly intravenous injection of synthetic vaccine particles carrying rapamycin (SVP-Rapa) during the first 3weeks of a 12-week course of ERT in GAA-KO mice, and compared this with three intraperitoneal injections of methotrexate (MTX) per week for the first 3weeks. Empty nanoparticles (NP) were used as negative control for SVP-Rapa. Co-administration of SVP-Rapa with rhGAA resulted in more durable inhibition of anti-rhGAA antibody responses, higher efficacy in glycogen clearance in skeletal muscles, and greater improvement of motor function than mice treated with empty NP or MTX. Body weight loss was observed during the MTX-treatment but not SVP-Rapa-treatment. Our data suggest that co-administration of SVP-Rapa may be an innovative and safe strategy to induce durable immune tolerance to rhGAA during the ERT in patients with Pompe disease, leading to improved clinical outcomes.

Authors:Sarah E. Anderson; Christopher E. BartonPages: 42 - 45Abstract: Publication date: December 2017 Source:Molecular Genetics and Metabolism Reports, Volume 13 Author(s): Sarah E. Anderson, Christopher E. Barton Cardiac glycosides are plant-derived molecules that have shown antiproliferative properties against cancer cells, though the mechanism of action is not completely understood. We show that one cardiac glycoside, convallatoxin, presents antiproliferative effects against colorectal cancer cells in culture and that the resulting cell death is independent of the p53 tumor suppressor. Our data suggest that convallatoxin may be useful in the treatment of cancers that harbor inactivating mutations in the p53 signaling pathway.

Authors:Alicia de la Parra; María Ignacia García; Valerie Hamilton; Carolina Arias; Juan Francisco Cabello; Verónica CornejoPages: 90 - 94Abstract: Publication date: December 2017 Source:Molecular Genetics and Metabolism Reports, Volume 13 Author(s): Alicia de la Parra, María Ignacia García, Valerie Hamilton, Carolina Arias, Juan Francisco Cabello, Verónica Cornejo There is a consensus on the importance of early and life-long treatment for PKU patients. Still, differences exist on target blood phenylalanine (Phe) concentrations for children with PKU in different countries and treatment centers. For the first time, long-term metabolic control and child development and cognitive functioning is compared between children with mean phenylalanine concentrations under 240μmol/L (group A), between 240 and 360μmol/L (group B) or over 360μmol/L (group C) during their first year of life. METHODS: 70 patients diagnosed with PKU through neonatal screening with Phe >900μmol/L, were divided into 3 groups: A, B and C, according to mean Phe concentrations and standard deviation (SD). Metabolic control during childhood, psychomotor development and IQ were compared. RESULTS: In group A, Phe was maintained within the recommended range until 6years of age, in Group B, until 3years of age, and in group C, Phe was always over the recommended range. No significant differences were found between the three groups in mental development index (MDI) and motor development index (PDI) scores at 12, 24, and 30months of age, but group C had the lowest scores on MDI at all age periods. At preschool and school age, IQ was higher in group A compared to group C. CONCLUSION: Results show that mean blood Phe concentrations between 120 and 240μmol/L during first year of life have a positive impact in metabolic control and cognitive functioning during childhood.

Authors:Mairead McLoughlin; Karolina Stepien Briony McNelly Lorraine Thompson Janet GortonAbstract: Publication date: December 2017 Source:Molecular Genetics and Metabolism Reports, Volume 13 Author(s): Mairead McLoughlin, Karolina M. Stepien, Briony McNelly, Lorraine Thompson, Janet Gorton, Christian J. Hendriksz Port-a-cath is a widely used device in patients with long-term venous access demand such as frequent or continuous administration of medications such as Enzyme Replacement Therapy (ERT), chemotherapy delivery, blood transfusions, blood products, and fluids. Patients with Lysosomal Storage Diseases (LSDs) often require recurrent courses of ERT. We reviewed our experience of using port-a-caths in patients with LSDs with the focus on challenges and complications associated with these catheters. Among 245 adult patients who were treated with ERT, twenty patients (8.2%) had a port-a-cath inserted due to poor venous access. Six patients were using their first port whereas five other patients had their port-a-caths replaced at least once. The remaining six patients had inactive port-a-caths. The majority of patients with active port-a-caths never missed more than one consecutive infusion, although one patient missed 2 consecutive infusions whilst on holiday. We identified significant gaps in patients' and their families' understanding of the management of port-a-caths and risks associated with them. It resulted in producing a leaflet and designing an educational program for our LSD patients.